Systems and methods for delivery of a therapeutic agent

ABSTRACT

Methods and apparatus are provided for applying an fragment of a neurotoxin such as the active light chain (LC) of the  botulinum  toxin (BoNT), such as one of the serotype A, B, C, D, E, F or G  botulinum  toxins, via permeabilization of targeted cell membranes to enable translocation of the  botulinum  neurotoxin light chain (BoNT-LC) molecule across the targeted cell membrane to the cell cytosol where a therapeutic response is produced in a mammalian system. The methods and apparatus include use of catheter based delivery systems, non-invasive delivery systems, and transdermal delivery systems.

RELATED APPLICATIONS

This application is a continuation of application Ser. No. 14/601,529filed Jan. 21, 2015, which in turn is a continuation of application Ser.No. 13/660,629 filed Oct. 25, 2012, now U.S. Pat. No. 8,961,391 issuedFeb. 24, 2015, in turn which is a continuation of application Ser. No.13/253,595 filed Oct. 5, 2011, now U.S. Pat. No. 8,338,164 issued Dec.25, 2012, which in turn is a continuation of application Ser. No.12/559,278 filed Sep. 14, 2009, now U.S. Pat. No. 8,133,497 issued Mar.13, 2012, which in turn is a divisional of application Ser. No.11/459,090 filed Jul. 21, 2006, now U.S. Pat. No. 7,608,275 issued Oct.27, 2009, which claims the benefit of U.S. Provisional Application No.60/702,077 filed Jul. 22, 2005, each of which is hereby fullyincorporated herein by reference.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to methods and apparatus for the controlof autonomic nerve function comprising delivery via permeabilization oftargeted cell membranes a therapeutically effective amount of a portionor fragment of a neurotoxin such as botulinum toxin (BoNT), the activeportion known as the light chain (LC), to cause a clinical benefit invarious regions within the body.

First used for medical purposes over 20 years ago for treatment ofblepharospasm and strabismus and other skeletal muscle abnormalities,certain neurotoxins have found widespread use in millions of patientsworldwide for a variety of conditions.

Controlled injection of neurotoxins has become a common procedure tocontrol skeletal muscle spasms. While the primary application ofneurotoxins such as BOTOX®, commercially sold by Allergan, Inc. (Irvine,Calif.), has been focused on cosmetic applications, such as treatment offacial wrinkles, other uses for the compound are now common. Certainapplications include treatment of cervical dystonia, tremor, headache(migraine), spasticity, torticollis, hemifacial spasm, blepharospasm,meige syndrome, spastic dysphonia, writers cramp, hyperhydrosis,hypersalivation, bladder dysfunction multiple sclerosis, spinal cordinjury, cystic fibrosis, stroke paralysis, stuttering, and all types ofpain.

Clostridium botulinum neurotoxins (BoNTs) block the release ofacetylcholine from peripheral cholinergic nerve endings therebydisabling the release of neurotransmitters from the cells (Bigalke, H.and Shoer, L. F. (1999) Clostridial Neurotoxins in Handbook ofExperimental Pharmacology 45, 407-443). This mechanism of action is welldefined. Seven immunologically distinct serotypes of neurotoxin,designated types A through G, have been identified as discussed bySimpson, L. L., Schmidt, J. J. and Middlebrook, J. L. (1988) in MethodsEnzymol. 165, 76-85. There are general structural and functionalsimilarities among the various types of neurotoxins, but they all havepreferred recipients, for example some favor use in humans and other innon-human species.

A frequently used neurotoxin for many applications in the human body isBotulinum Toxin Type A (BoNT\A), a protein produced by the bacteriumClostridium botulinum and sold commercially by Allergan, inc., asBOTOX®. Botulinum toxin blocks the release of neurotransmitter from thenerves that control the contraction of the target muscles. When used inmedical settings, small doses of the toxin are injected into theaffected muscles and block the release of a chemical acetylcholine thatsignals the muscle to contract. The toxin thus paralyzes or weakens theinjected muscle.

In addition, use of neurotoxin for control of the following conditionshas been proposed in U.S. Pat. No. 6,063,768 to First, and U.S. Pat. No.5,766,605 to Sanders, including: rhinorrhea, asthma, COPD, excessivestomach acid secretion, spastic colitis, otitus media, arthritis,tensoynovitis, lupus, connective tissue disease, inflammatory boweldisease, gout, tumors, musculo-skeletal abnormalities, reflexsympathetic dystrophies, tendonitis, bursitis, and peripheralneuropathy. Various other patents contemplate the use of a neurotoxinfor additional applications such as, neuromuscular disorders (U.S. Pat.No. 6,872,397), essential tremor (U.S. Pat. No. 6,861,058), pancreatitis(U.S. Pat. No. 6,843,998), muscle spasm (U.S. Pat. No. 6,841,156), sinusheadache (U.S. Pat. No. 6,838,434), endocrine disorders (U.S. Pat. No.6,827,931), priapism (U.S. Pat. No. 6,776,991), thyroiditis (U.S. Pat.No. 6,773,711), cardiovascular disease (U.S. Pat. No. 6,767,544),thyroid disorders (U.S. Pat. No. 6,740,321), hypocalcemia (U.S. Pat. No.6,649,161), hypercalcemia (U.S. Pat. No. 6,447,785), tardive dyskenesia(U.S. Pat. No. 6,645,496), fibromyalgia (U.S. Pat. No. 6,623,742),Parkinson's Disease (U.S. Pat. No. 6,620,415) cerebral palsy (U.S. Pat.No. 6,448,231), inner ear disorders (U.S. Pat. No. 6,358,926), cancers(U.S. Pat. No. 6,139,845), otic disorders (U.S. Pat. No. 6,265,379),appetite reduction (US2004/0253274), compulsive disorders(US2004/0213814, US2004/0213813), uterine disorders (US2004/0175399),neuropsychiatric disorders (US2003/0211121), dermatological ortransdermal applications (US2004/00091880), focal epilepsy(US2003/0202990) the contents of which are expressly incorporated hereinby reference in their entirety.

The patent authors have further detailed devices and methods fortreating asthma with local delivery of the intact botulinum toxin inU.S. patent application Ser. No. 10/437,882, filed on May 13, 2003, thecontents of which are expressly incorporated by reference herein in itsentirety.

Due to their extreme toxicity, neurotoxins are highly controlled and canhave disastrous consequences if not used and controlled properly,especially when used in vivo. In addition, due to their toxicity, thebody tends to build up a resistance to their use, resulting in lowerefficacy, the need for increased treatments, or the need to discontinuetheir use all together in certain patients.

In light of the foregoing, it would be desirable to provide methods andapparatus for delivering neurotoxins such as botulinum toxinsnon-toxically.

It would also be desirable to provide methods and apparatus for treatingvarious conditions with a neurotoxin such as botulinum toxin fragmentsvia in vivo cell permeabilization.

In would also be desirable to provide a system of devices, includingcatheters, trocars, needles, endoscopes, inhalers, nebulizers andaerosolizers and other mechanisms to deliver fragmented neurotoxinsnon-toxically.

Further, it would be desirable to couple energy delivery devices withthe delivery of fragmented neurotoxins to deliver active neurotoxins,non-toxically, including catheter based energy systems, and non-invasiveenergy systems.

All publications and patents or patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent or patent application wasspecifically and individually so incorporated by reference.

BRIEF SUMMARY OF THE INVENTION

According to the present invention, an active fragment (sometimesreferred to as a catalytic portion) of a neurotoxin such as thebotulinum neurotoxin (BoNT), preferably the light chain (LC) portion ofBoNT, is delivered to target cells via cell membrane permeabilization.Such delivery provides a non-toxic delivery scheme for deriving avariety of clinical benefits. Although botulinum toxins are used broadlyfor a variety of clinical applications, the present invention providesenhanced methods of delivery and use of the isolated active fragments orportions of the toxin. Other neurotoxins which may be used in themethods and systems of the present invention include ricin and itsactive fragments, exotoxin A and its active fragments, diphtheria toxinand its active fragments, cholera toxin and its active fragments,tetanus toxin and its active fragments, and the like.

The present invention contemplates application to all of the conditionslisted herein, collectively defined as “therapeutic target conditions”,and any other conditions for which BoNT and other neurotoxins are knownto or can be shown to provide a therapeutic benefit. Certain exampleshave been detailed below for specific applications, but it is within thescope of the present invention that the methods and devices detailedherein have specific applications to many or all of the conditionswherein the intact neurotoxins have shown or proposed to show atherapeutic benefit or effect.

In one aspect of the present invention, BoNT-LC or other activeneurotoxin fragment is delivered with the application of energy toachieve cell membrane permeabilization.

In another aspect of the present invention methods and apparatus areprovided for altering autonomic nerve function by utilizing an electricfield or ultrasonic energy generated by a pulse or pulses of adesignated duration and amplitude to alter tissue at the cellular levelvia permeabilization of the cell membrane to facilitate thetranslocation of the BoNT-LC or other active neurotoxin fragment to thecell cytosol.

A further aspect of the invention is to provide methods and apparatusfor treating or inhibiting a variety of diseases or syndromes that havean underlying neurogenic component, by disrupting the neurogenicactivities of the promoters or mediators of the disease or syndrome.Such disruption is facilitated by delivering an active fragment ofbotulinum toxin, such as the light chain portion of botulinum toxinserotype A (BoNT-LC/A), in the presence of an electric field orultrasonic energy applied to permeabilize the wall of targeted cellunder conditions which induce reversible poration of the cellularmembrane and efficient passage of the BoNT-LC fragment to the cellcytosol, its catalytic environment.

In addition to the methods described thus far, the present inventionfurther provides systems for delivering toxins to target cells in amammalian host. The target cells may be in any of the target regionsdescribed above or in any other target region which may benefit from thespecific and enhanced delivery of a neurotoxin to cells within theregion. Systems comprise catheter or other structure adapted tointroduce the toxin or toxin fragment to a region adjacent the targetcells. The systems further comprise an energy applicator for applyingenergy to the target cells under condition which cause poration of thecell membranes to enhance delivery of the toxins and/or their activefragments. The systems still further comprise a source of the toxin oractive fragments suitable for introduction from the catheter or otherdelivery structure.

The energy applicator will typically be adapted to selectively applyenergy to target cells within the region where the toxin is to beintroduced, e.g., by focusing energy distribution to the particulartarget cells or regions which are rich with the target cells.Alternatively, the energy applicator may be adapted to apply energynon-selectively within the target region where both target cells andother cell types may receive the energy.

In some instances, the toxin may comprise an intact toxin, but moreusually will comprise an active toxin fragment as defined elsewhere inthis application. In the exemplary embodiments, the active toxinfragment is the light chain fragment of the botulinum toxin (BoNT-LC).The light chain fragment may be derived from any one of at leastbotulinum toxins A, B, C, D, E, F, and G.

The energy applicators of the systems of the present invention may beadapted to apply electric energy, typically pulses between 1 V and 500 Vto the targeted region. The electric energy may be radiofrequency (RF)energy, where the energy may be pulsed for durations between 5microseconds to 100 milliseconds. Alternatively, the electrical energycan be direct current (DC), alternating current (AC), or combinationsthereof.

In addition to electrical energy, the energy applicator may be adaptedto deliver ultrasonic energy, X-ray beam energy, microwave energy, orany other energy type which can achieve a reversible poration of thetarget cell walls.

There are at least two general power categories of medical ultrasoundwaves which may be utilized in the present invention. One category ofmedical ultrasound wave is high acoustic pressure ultrasound. Anothercategory of medical ultrasound wave is low acoustic pressure ultrasound.Acoustic power is expressed in a variety of ways by those skilled in theart. One method of estimating the acoustic power of an acoustic wave ontissue is the Mechanical Index. The Mechanical Index (MI) is a standardmeasure of the acoustic output in an ultrasound system. High acousticpressure ultrasound systems generally have a Ml greater than 10. Lowacoustic pressure systems generally have a MI lower than 5. For example,diagnostic ultrasound systems are limited by law to a Mechanical Indexnot to exceed 1.9. Another measurement used by those skilled in the artis the spatial peak, peak average intensity (Isppa). The intensity of anultrasound beam is greater at the center of its cross section than atthe periphery. Similarly, the intensity varies over a given pulse ofultrasound energy. Isppa is measured at the location where intensity ismaximum averaged over the pulse duration. Isppa for high acousticpressure or high intensity focused ultrasound (HIFU) applications rangesfrom approximately 1500 W/cm² to 9000 W/cm². Diagnostic ultrasoundequipment, for instance, will generally have, and an Isppa less than 700W/cm². Yet another way in which ultrasound waves can be characterized isby the amplitude of their peak negative pressure. High acoustic pressureor HIFU applications employ waves with peak amplitudes in excess of 10MPa. Low acoustic pressure ultrasound will generally have peak negativepressures in the range of 0.01 to 5.0 MPa. Diagnostic ultrasoundequipment, for example, will generally have a peak amplitude less than3.0 MPa. Both high and low acoustic pressure ultrasound systemsgenerally operate within the frequency range of 20 KHz-10.0 MHzInterventional applications (such as in blood vessels) operateclinically up to about 50 MHz. Also opthalmologic applications up toabout 15 MHz. Diagnostic imaging typically uses frequencies of about 3to about 10 MHz. Physical therapy ultrasound systems generally operateat frequencies of either 1.0 MHz or 3.3 MHz. High acoustic pressureultrasound or high intensity focused ultrasound has been used for tissuedisruption, for example for direct tumor destruction. High intensityfocused ultrasound using high acoustic pressure ultrasound is mostcommonly focused at a point in order to concentrate the energy from thegenerated acoustic waves in a relatively small focus of tissue.

Systems and methods for permeabilization of target tissue cell membranesaccording to the present invention may employ either high acousticpressure or low acoustic pressure ultrasound. Some embodiments maypreferably employ relatively low acoustic pressure, for example thesystems described herein where the transducers are mounted on thedelivery devices and operate inside the body. Other systems may operateat interim acoustic pressure ranges. For example, systems describedherein which employ an external ultrasound generator and transducer andwhich conduct the ultrasound to the target tissues through the use of awave guide. In these systems, losses due to transduction through thewave guide can be compensated for by increasing the input power to thewave guide until adequate power is delivered to the target tissue.Finally, some systems described herein may employ focused or partiallyfocused higher pressure ultrasound, for example the systems which employan external mask to conduct the ultrasonic power through the tissues tothe target tissues. It should be appreciated that combinations of highand low acoustic pressure systems may also be employed.

The catheter or other structure may be adapted to introduce the toxin tothe target cells in a variety of ways. For example, catheters maycomprise a needle for injecting the toxin, optionally a needle which isdeployable axially or radially from the catheter body. Alternatively oradditionally, catheters may be provided with nozzles or other ports foraerosolizing the toxin, particularly within regions of the lung asdescribed herein. Still further alternatively or additionally, thecatheters may comprise balloons or other expandable elements fordeflecting an end of the catheter to engage one or more ports on thecatheter against the tissue where the toxin fragments are releasedthrough the port(s). In a specific embodiment, the ports may be in theballoon itself where the toxin fragments are released through the portsin the balloon as the balloon is inflated with the medium containing thefragments. With such balloon embodiments, the electrodes or other energytransducers will typically be located within the balloon for applyingthe poration energy to the target tissue. Further optionally, the energyapplicators may be mounted directly on the catheters, for example in theform of acoustic transducers, RF or other electrical electrodes, or thelike. Alternatively, the energy applicator may be provided separatelyfrom the toxin delivery catheter or other source, typically being anexternal source, such as an external high intensity focused ultrasound(HIFU) source or an external electrode array for deliveringradiofrequency or other electroporation energy.

In a further aspect of the invention, it may be desirable to providemethods and devices that utilize a non-toxic delivery mechanism totarget cells to reduce the potential for an immunogenic response to thedelivered toxin over time.

In a further aspect of the invention, it may be desirable to deliver thetherapeutic neurotoxin fragment and energy via a catheter.

In a further aspect of the invention, it may be desirable to deliver thetherapeutic neurotoxin fragment via an aerosolizer or nebulizer.

In a further aspect of the invention, it may be desirable to deliver thetherapeutic neurotoxin fragment via an inhaler.

In a further aspect of the invention, it may be desirable to deliver thetherapeutic neurotoxin fragment and membrane transport energytransdermally.

In a further aspect of the invention, it may be desirable to deliver thetherapeutic neurotoxin fragment via a catheter, or aerosolizer orinhaler, and the energy via a catheter placed in the vicinity of thetargeted cell.

In a further aspect of the invention, it may be desirable to deliver thetherapeutic neurotoxin fragment and the membrane transport energy via animplantable generator and drug delivery pump.

In a further aspect of the invention, it may be desirable to deliver thetherapeutic neurotoxin fragment via a catheter, or aerosolizer(nebulizer) or inhaler, and the energy via an external energy sourceadapted to target the applied energy in the vicinity of the targetedcell.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features of the invention, its nature and various advantageswill be more apparent from the accompanying drawings and the followingdetailed description, in which:

FIG. 1—depicts a schematic of the creation of neurotoxin Botulinum ToxinType A (BoNT/A), including the light chain (LC) fragment or portion.

FIG. 2A—depicts a schematic of a target cell, including the cellmembrane, and inner cellular matrices.

FIG. 2B—depicts a schematic of the target cell wherein LC molecule hasbeen introduced.

FIG. 3A-3B—depicts a the target cell of FIG. 2 showing application of anenergy field (EF) to produce permeabilization or pores (P) in the cellmembrane, and introduction of the LC fragment therethrough.

FIG. 4—depicts a schematic of a cell wherein the energy field has beendiscontinued, and neurotransmission of the cell has been effectivelyblocked.

FIGS. 5, 5A-5B—depicts various embodiments of a delivery device of thepresent invention utilizing multiple energy transmission elements and anenergy transmission system.

FIGS. 6A-D, 6AA, and 6CC—depict various electrode catheterconfigurations adapted to deliver energy or energy and therapeuticagents to target tissue.

FIG. 7—depicts an alternative embodiment of the present inventionwherein one of the multiple energy transmission elements is placed atthe targeted cell site, and the other in a location remote therefrom.

FIG. 8—depicts an embodiment of the present invention utilizing anultrasound element on a catheter device.

FIG. 9—depicts an embodiment of the present invention utilizing aninhaler with an in vivo energy delivery source.

FIG. 10—depicts an interstitial method of use of the present invention.

FIG. 11—depicts an embodiment of the present invention utilizing anaerosolizing element.

FIG. 12—depicts a fully implantable pulse generator, lead and agentdelivery pump of the present invention.

FIG. 13—depicts an embodiment of the present invention utilizing anexternal energy delivery source applied to the therapeutic agent appliedin the vicinity of a targeted cell.

FIG. 14—depicts an embodiment of the present invention wherein theenergy and therapeutic agent are delivered transdermally.

FIG. 15—depicts a method of use of a noninvasive agent delivery devicecoupled with a non-invasive energy source for treating a lumen or tractof the respiratory system.

FIGS. 15A and 15B—depict use of a balloon for delivering toxin fragmentsin a lung.

FIGS. 16A and 16B—depict use of a deflected catheter tip for deliveringtoxin fragments in a lung.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to methods and apparatus for targetingthe non toxic delivery of a fragment of a neurotoxin, while stillmaintaining the catalytic or toxic effect of the neurotoxin fragmentonce it is non-toxically delivered to its targeted cell. For purposes ofthis specification, the term “non-toxic”, “non-toxically” and the likerefer to the state of the fragment molecule prior to delivery to atarget location. In this description, the fragment neurotoxin isintended to retain its toxic effect once delivered to its catalyticenvironment; the intracellular matrix or cytosol of the targeted cell.

Devices and methods of the present invention may be directed to suitable“targeted regions” such as muscle cells in various regions of the bodyrelated to the various “therapeutic target conditions” or syndromes tobe treated, as detailed in this specification above. Some particularexamples include targeting mucosal and muscular lining of the lung,cholinergic cells in the region of tumors, myofacial regions, vascularsmooth muscle cells, musculoskeletal regions and the like.

According to the present invention, energy fields (EF) may be applied totarget regions in conjunction with the delivery of a fragmentedneurotoxin such as BoNT-LC to facilitate the transfer of the neurotoxinfragment into the targeted cell, non-toxically via in vivo target cellpermeabilization.

Use of Isolated Light Chain of Botulinum Neurotoxins

Generally, the BoNT molecule is synthesized as a single polypeptidechain of 150 kD molecular weight. The neurotoxin is then exposed toenzymes, either during cultivation of the Clostridium botulinum organismor subsequent to purification of the toxin, wherein specific peptidebonds are cleaved or “nicked” resulting in the formation of a dichainmolecule referred to as BoNT. As shown in FIG. 1, dichain neurotoxin iscomposed of a light chain (LC) region 50 kD molecular weight linked bydisulfide bonds to a heavy chain (HC) 100 kD molecular weight (Kistner,A., Habermann, E. (1992) Naunyn Schmiedebergs Arch. Pharmacol. 345,227-334). When the light chain is separated from the heavy chains ofbotulinum toxin, neither chain is capable of blocking neurotransmitterrelease, however, the light chain alone is capable of blockingacetylcholine release if transported directly into the cell cytosol.(Ahnert-Hilger, G., Bader, M. F., Bhakdi, S., Gratzl, M. (1989) J.Neurochem. 52, 1751-1758 and Simpson, L. L. (1981) Pharmacol. Rev. 33,155-188.) Focusing on the light chain, the isolation or separationprocess essentially renders the light chain “non-toxic” in a generalenvironment, while still maintaining its effect or toxicity, once it istransported through the target cell membrane.

Over the past several years, the separation and purification of thelight chain and heavy chain of BoNT has seen significant developmentactivity. In the case of the heavy chain (HC), researchers areinterested in its ability to bond with a target cell and deliver certainmolecules into that cell. For example, various drug deliveryapplications have been suggested, for example, using the HC to bind totPA so that a patient could inhale the HC bound tPA allowing it to crossthe membrane of the lungs and be transported into the bloodstream foranticoagulation. Of particular interest to the present invention are theefforts to isolate and purify the light chain (LC) of the botulinummolecule. In its isolated and purified form, all HC elements areremoved, rendering the LC incapable of crossing the cell membranewithout assistance. Thus, the LC is non-toxic until delivered to thetarget cell cytosol by the delivery protocols of the present invention.

Various groups have been active in the area of isolation andpurification. For example, companies such as Metabiologics, a groupaffiliated with the University of Wisconsin, the Center for AppliedMicrobiology and Research (CAMR), a division of the UK Health ProtectionAgency, List Biological Laboratories, Inc. of California, and otherresearch groups throughout the world. Many of these companies providepurified preparations of botulinum neurotoxins from Clostridiumbotulinum types A and B. List Laboratories in particular providesrecombinantly produced light chains from both types A, B, C, D and E.

According to the present invention, the therapeutic use and delivery ofthe light chain only may significantly improve the safety profile ofcertain applications of therapies utilizing BoNT. BoNT are some of themost lethal toxins known to man. All concerns about migration of theneurotoxin into unintended regions, and harm or toxicity to the patientor physician are eliminated by storing, handling, injecting andmetabolizing the light chain only. In the absence of a specific membranebinding technology, the LC is completely non-toxic. In certainapplications, such as the treatment of asthma, this is of criticalimport. In using BoNT to treat asthma, a large quantity of the purifiedLC substance may be introduced directly into the lung, and thenspecifically transported to target cells in the exact location and onlyduring the period of use of application of the membrane transporttechnology, such as cell membrane permeabilization by energy. Once themembrane transport technology has been removed, turned off or otherwiseinactivated, the remaining LC which has not been transported into targetcells can simply be removed from the body by standard biologic processesfor expelling foreign materials, e.g. coughing, immune system orlymphatic system transport and the like.

In addition, therapeutic use of only the LC of the neurotoxin BoNT mayreduce the likelihood of the body developing an immunogenic response tothe therapy that is seen with delivery of the intact toxin. This couldbe a major advantage in light of the repetitive application or injectionof the toxin that is required to maintain a therapeutic effect.

Non-Toxic Membrane Transport Mechanisms

To date, the main application of purified or isolated light chain hasbeen the study of its mechanism of action. To further this research,literature has reported the use of certain detergent basedpermeabilization techniques to deliver fragment BoNT (Bittner M A,DasGupta B R, Holz R W. Isolated light chains of botulinum neurotoxinsinhibit exocytosis. Studies in digitonin-permeabilized chromaffin cells.J Biol Chem 1989 Jun. 25; 264(18):10354-10360.) Further reference to themechanism of permeability of cell membranes to deliver botulinum toxinare mentioned in U.S. Pat. No. 6,063,768 to First, and U.S. Pat. No.6,632,440 to Quinn, Chaddock, et al “Expression and Purification ofCatalytically Active Non-Toxic Endopeptidase Derivatives of Clostridiumbotulinum toxin type A”, Protein Expression and Purification, 25 (2002)219-228, contemplating the insertion of the light chain of BoNT into atarget cell without the heavy chain for purposes of deriving vaccines orin bench top studies of cell mechanisms of action. The contents of thesereferences are expressly incorporated by reference in their entirety.None of the teachings contemplate a delivery of a fragment of neurotoxinusing a clinically acceptable permeabilization technique in vivo fortherapeutic uses as is contemplated by the present invention.

For purposes of this specification, the term “poration” includes variousforms of electroporation, such as the use of pulsed electric fields(PEFs), nanosecond pulsed electric fields (nsPEFs), ionophoreseis,electrophoresis, electropermeabilization, as well as other energymediated permeabilization, including sonoporation (mediated byultrasonic or other acoustic energy), and/or combinations thereof, tocreate temporary pores in a targeted cell membrane. Similarly, the term“electrode” or “energy source” used herein, encompasses the use ofvarious types of energy producing devices, including x-ray,radiofrequency (RF), DC current, AC current, microwave, ultrasound,adapted and applied in ranges to produce membrane permeabilization inthe targeted cell.

Reversible electroporation, first observed in the early 1970's, has beenused extensively in medicine and biology to transfer chemicals, drugs,genes and other molecules into targeted cells for a variety of purposessuch as electrochemotherapy, gene transfer, transdermal drug delivery,vaccines, and the like.

In general, electroporation may be achieved utilizing a device adaptedto activate an electrode set or series of electrodes to produce anelectric field. Such a field can be generated in a bipolar or monopolarelectrode configuration. When applied to cells, depending on theduration and strength of the applied pulses, this field operates toincrease the permeabilization of the cell membrane and reversibly openthe cell membrane for a short period of time by causing pores to form inthe cell lipid bilayer allowing entry of various therapeutic elements ormolecules, after which, when energy application ceases, the poresspontaneously close without killing the cell after a certain time delay.As characterized by Weaver, Electroporation: A General Phenomenon forManipulating Cells and Tissues Journal of Cellular Biochemistry,51:426-435 (1993), short (1-100 .mu·s) and longer (1-10 ms) pulses haveinduced electroporation in a variety of cell types. In a single cellmodel, most cells will exhibit electroporation in the range of 1-1.5Vapplied across the cell (membrane potential).

In addition, it is known in the art that macromolecules can be made tocross reversibly created pores at voltages of 120V or less applied tocells for durations of 20 microseconds to many milliseconds. Forapplications of electroporation to cell volumes, ranges of 10 V/cm to10,000 V/cm and pulse durations ranging from 1 nanosecond to 0.1 secondscan be applied. In one example, a relatively narrow (pee) high voltage(200V) pulse can be followed by a longer (>msec) lower voltage pulse(<100V). The first pulse or series of pulses open the pores and thesecond pulse or series of pulses assist in the movement of the BoNT-LCacross the cell membrane and into the cell.

Certain factors affect how a delivered electric field will affect atargeted cell, including cell size, cell shape, cell orientation withrespect to the applied electric field, cell temperature, distancebetween cells (cell-cell separation), cell type, tissue heterogeneity,properties of the cellular membrane and the like.

Various waveforms or shapes of pulses may be applied to achieveelectroporation, including sinusoidal AC pulses, DC pulses, square wavepulses, exponentially decaying waveforms or other pulse shapes such ascombined AC/DC pulses, or DC shifted RF signals such as those describedby Chang in Cell Potation and Cell Fusion using and Oscillating ElectricField, Biophysical Journal October 1989, Volume 56 pgs 641-652,depending on the pulse generator used or the effect desired. Theparameters of applied energy may be varied, including all or some of thefollowing: waveform shape, amplitude, pulse duration, interval betweenpulses, number of pulses, combination of waveforms and the like.

A schematic example of the methods of the present invention are shown inFIGS. 2-4 in a simplified single cell model. A targeted cell 10 is shownin FIG. 2A. Fragmented neurotoxin such as BoNT-LC (LC) is introducedinto the vicinity of the targeted cell as depicted in FIG. 2B. An energyfield (EF) is applied in accordance with the present invention resultingin the transfer of the BoNT-LC through pores P to the intracellularmatrix (cytosol) as shown in FIGS. 3A and 3B. Once this transfer hasoccurred, the release of neurotransmitters of the target cell are thenblocked or disrupted, and once energy application is discontinued, thepores P in the cell membrane recover or close as depicted in FIG. 4.

Of particular interest for application in certain therapeutic targetconditions is the developing field of sonoporation. Just as pulses ofhigh voltage electricity can open transient pores in the cell membrane,ultrasonic energy can do the same. See for example Guzman et al.“Equilibrium Loading of Cells with Macromolecules by Ultrasound: Effectsof Molecular Sizing and Acoustic Energy,” Journal of PharmaceuticalSciences, 91:7, 1693-1701, which examines the viability of ultrasound todeliver molecules of a variety of sizes into target cells. In addition,techniques for nebulizing fluids and aqueous drugs are well known in theart, and as such, devices of the present invention may be adapted tointroduce a BoNT-LC solution to a target region, such as the lung andthen effect selective membrane transport of the BoNT-LC into the cellusing sonoporation.

For example, U.S. Pat. No. 6,601,581 to Babaev, hereby incorporated byreference in its entirety, describes certain techniques for deliveringtherapeutic agents using ultrasound for pulmonary delivery via anaerosolizing technique. Further, Guzman, et al, depicts delivery ofmolecules from a low of 62 Da up to 464 kDa (a range of 0.6-18.5 nmradius). Since the LC of the botulinum toxin is in the 50 kDa range, theLC would be very susceptible to sonoporetic delivery. Furthermore,Guzman, et al also showed that for all size ranges tested, levels ofmacromolecule within the cell reached thermodynamic equilibrium with theextracellular environment, and the cell uptake also depended on theenergy delivered, as expressed in J/cm2. As such, the sonoporeticdelivery of LC to the targeted regions may be controlled by adjustingthe concentration of the LC exposed to the target region (e.g. wall ormembrane of the lung), the energy delivered to the target region, orboth.

Catheter Devices

To achieve the goals of the present invention, it may be desirable toemploy methods and apparatus for achieving cell membranepermeabilization via the application of an energy source, either from acatheter located directly in the vicinity of the targeted cells, or anexternally focused energy system. For purposes of this specification,the term “catheter” may be used to refer to an elongate element, hollowor solid, flexible or rigid and capable of percutaneous introduction toa body (either by itself, or through a separately created incision orpuncture), such as a sheath, a trocar, a needle, a lead. Furtherdescriptions of certain electroporation catheters are described in U.S.Patent Application 60/701,747, filed on Jul. 22, 2005, the fulldisclosure of which is expressly incorporated herein by reference.

FIGS. 5 and 5A-5B depict a system 20 utilizing an electroporationcatheter 22 for selective electroporation of targeted cells. In certainconfigurations of the present invention, voltages may be applied via theelectroporation catheter 22 to induce reversible electroporation at thesame time as the catheter delivers the fragmented neurotoxin to thetargeted region.

Referring to FIG. 5, electroporation catheter system 20 furthercomprises a pulse generator 24 such as those generators available fromCytopulse Sciences, Inc. (Columbia, Md.) or the Gene Pulser Xcell(Bio-Rad, Inc.), or IGEA (Carpi, Italy), electrically connected to acatheter having a proximal end and a distal end and adapted forminimally invasive insertion into the desired region of the body asdescribed herein. The catheter further comprises an electroporationelement 26 at a distal 28 end thereof. The electroporation element mayinclude for example a first and second electrode 30 and 32 operativelyconnected to the pulse generator for delivering the desired number,duration, amplitude and frequency of pulses to affect the targetedcells. These parameters can be modified either by the system or theuser, depending on the location of the catheter within the body(intervening tissues or structures), and the timing and duration ofreversible cell poration desired. FIG. 5A depicts an arrangement ofelectrodes 30 and 32 that produces an electric field concentrated in alateral direction from the catheter body whereas, FIG. 5B shows a deviceconstructed to create a more uniform electric field about the shaft ofthe catheter body.

Further catheter device and electrode configurations are shown in FIGS.6A-6D. FIG. 6A depicts an elongate catheter 40 having first and secondelectrodes 42 and 44 near the distal tip thereof, and including amonitoring or stimulation electrode 46 in the vicinity of the activeporating electrodes for localizing the treatment area. In someembodiments, the monitoring or stimulating function may be performed byone or more of the treatment electrodes. The catheter device may have anoptional sharp tip 48 to facilitate percutaneous introduction.Cross-sectional view FIG. 6A A shows various lumens provided forneurotoxin fragment delivery and other purposes.

FIG. 6B is a similar catheter device 50 having electrodes 52, 54, and56, but is further adapted to be steerable, or articulate at a region 53near the distal end of the device, e.g., including a pull wire fordeflecting the tip. Such steering ability enables the operator tointroduce the device into tight or tortuous spaces (such as thebronchial passages or cardiovascular vessels) so that optimal placementof the device at the target location may be achieved.

FIG. 6C depicts a catheter device 60 having a needle 62 or otherinjection element to allow for the injection of a therapeutic agent suchas a fragmented neurotoxin before, during or after the application ofthe pulsed energy or electroporation. The catheter 60 further includeselectrodes 64 and 66 or other poration components as discussed herein.The injection element may be a needle 62 as shown in FIG. 6C, aninfusion port, or other infusion means. Needle 62 may also be used as anelectrode in addition to an injection port. Electrode 68 comprises amonitoring or stimulating electrode. FIG. 10 depicts the use of acatheter of FIG. 6C to treat bronchial tissue in the lung for a varietyof respiratory ailments such as asthma. FIG. 6CC is a cross-sectionalview taken along line 6CC-6CC in FIG. 6, showing a co-axial sleevedesign.

FIG. 6D depicts a catheter device 70 having electrode elements 72 and 74that are adapted to extend laterally from the main catheter body, and insome cases, penetrate the surrounding tissue prior to application ofenergy. In doing so the depth and direction of the energy field createdby the electroporative process, may be further controlled. Amonitoring/stimulating electrode 76 will usually also be provided.Elements 72 and 74 may also be used as injection ports for introductionof toxin or toxin fragments.

FIG. 7 depicts the use of a catheter device 80 of the present inventionfor treatment of a respiratory tract, by positioning at least oneelectrode (82) at the target region, and a second electrode (84) remotefrom the target region, the target region being positioned between 82and 84, such that activation of the electrodes produces an energy field(EF) therebetween, the size and intensity of which can be controlled bythe placement of the electrodes relative to each other and the targetedregion.

FIG. 8 depicts catheter 90 constructed in accordance with the principlesof the present invention utilizing an ultrasonic element 92 that may beparticularly useful in delivery of the BoNT-LC to bronchial tissue(lung) that provides a broad but targeted transport of the LC across thetarget cell walls, for example, epithelial and goblet cell walls. Inthis device, ultrasound energy is delivered to the distal end of thecatheter device via an ultrasonic waveguide 94 that is operativelyconnected to an ultrasound energy source (U/SES). The LC fragment wouldbe delivered from a receptacle 96 via the same lumen as the waveguidevia a lumen provided the distal tip of the device. In operation, theultrasonic energy would cause the LC solution to be nebulized, forming amist or aerosol 98 within the lung, as shown in FIG. 11. The aerosol 98itself, in the appropriate concentrations, may act as an ultrasoundcoupler, conveying the ultrasonic energy to the wall of the lung orother targeted cellular structures, causing sonoporation of the targetedcells whereby the LC fragment is transmitted across the cell membranesto become an effective neurotransmitter blocker. In an alternativeembodiment, an ultrasonic transducer may be located directly at the tipof the delivery device, eliminating the need for a wave guide. Variouscatheters useful for delivering vibrational energy to tissue aredescribed in U.S. Pat. Nos. 6,361,554 and 6,464,680 to Brisken, thecontents of which are expressly incorporated herein by reference intheir entirety, for various therapeutic effects, such as enhancingcellular absorption of a substance.

Since air is a very effective insulator against transmission ofultrasonic energy, the treatment area in the lung may be more preciselycontrolled by the concentration of the LC mist and the intensity of theultrasonic energy. A fairly steep drop off in energy delivery wouldoccur as mist concentration diffused, effectively protecting areasoutside the predetermined radius surrounding the distal end of thedelivery device. According to the present invention, since no functionalneurotoxin exists without an effective membrane transport technology,terminating the energy application leaves a harmless mist that is thencoughed up (if resident in the lungs) or otherwise metabolized andexcreted by the body.

Any of the catheter devices described herein, or described in thecontemporaneously filed U.S. Patent Application 60/701,747, previouslyincorporated by reference in its entirety, may be adapted to include anenergy delivery element such as those described herein for purposes ofproviding a membrane transport system for delivery of a fragment ofneurotoxin. In addition, certain catheter devices and methods such asthose set forth in U.S. Pat. Nos. 5,964,223 and 6,526,976 to Baran maybe adapted to include energy transmission elements capable of producinga porative effect at the cellular level, including electrodes,ultrasonic elements and the like, for treatment in the respiratorytract.

Furthermore, any of the foregoing systems may include electrodes orother monitoring systems either located on the treatment catheter, orexternal to the patient, to determine the degree of treatment to theregion, including, thermocouple, ultrasound transducers, fiberoptics,sensing or stimulating electrodes. Further, it may be desirable toincorporate multiple pairs of electrodes that may be activated in pairs,in groups, or in a sequential manner in order to maximize the desiredshape of the energy field (EF) while minimizing the field strengthrequirements.

Implantable Devices

Just as energy may be delivered to a targeted region to facilitate thedelivery of fragmented neurotoxin via a catheter system, it is alsowithin the scope of the present invention to deliver neurotoxins via animplantable system, including a pulse generator, lead and drug pump asdepicted in FIG. 12. A neuromodulation system 200 may be fullyimplantable, having a pulse generator and a power supply or battery andbe operatively connected to a programmable drug delivery pump all housedwithin a module 202, including a reservoir in which the BoNT-LC isstored for delivery over time using the principles of the presentinvention and technology of the programmable drug pump. A catheter 204can be adapted to deliver the drug and poration energy to a desiredtarget location in the patient's body.

Examples of useful implantable devices of the present invention arc,devices such as those set forth in U.S. Pat. No. 5,820,589 to Torgersonet al, the entire contents of which are hereby incorporated byreference, the SynchroMed® programmable pump available from Medtronic,Inc. (Minneapolis, Minn.), and the neurostimulation units such as theRESTORE* or SynergyPlus® available from Medtronic, Inc., modified ifnecessary to deliver the desired voltage range for cell membranepermeabilization. Implantation of the neurostimulation device is furtherdescribed in U.S. Pat. No. 6,847,849, incorporated herein by referencein its entirety.

The non-toxic nature of the BoNT in the absence of applied energy makesit possible to contemplate placing a bolus of neurotoxin in the body ofa patient in what might otherwise be a toxic amount. This isparticularly advantageous, since the traditional treatment regime usingneurotoxins, is typically repeat injections of the toxins every 3 to 6months and sometimes more frequently depending on the application.Certainly in more chronic conditions such as chronic pain, tremor,spasm, palsy and the like, such a fully implantable system may be highlydesirable.

Non-Invasive Devices

It is within the scope of the invention to deliver either the energy orthe therapeutic BoNT-LC non-invasively, or both. For example, FIG. 13depicts delivery of the BoNT-LC via a catheter 100 placed in thebronchial passageway with the energy field (EF) delivered from outsidethe patient in the form of an energy system 102 such as focusedultrasound (HIFU), stereotactic x-ray beams, magnetic resonancetransmission, and the like. As detailed in U.S. Pat. Nos. 6,626,855 and6,719,694 to Weng, the contents of which are expressly incorporatedherein by reference in their entirety, an ultrasound beam can becontrolled from outside the patient to focus the ultrasound beam in thedesired location and intensity. For use in the present invention, it maybe desirable to pulse or otherwise attenuate the ultrasound beam toachieve reversible cellular poration at the targeted site. Further, dueto its non-toxic state, the BoNT-LC may be inhaled by the patient usinga standard inhaler device such as those using pressurized aerosols knownas metered dose inhalers (MDI) available from Cardinal Health (Somerset,N.J.), the OPTIHALER® available from National Allergy SupplyIncorporated (Georgia, USA), or a nebulizer breathing machine such as aPari DURANEB 3000 portable nebulizer available from Medinfinity, Co.(Fountain Valley, Calif.). In addition, certain technology currentlyunder development employing thermal aerosols, such as a the STACCATO™vaporization technology from Alexza Molecular Delivery (Palo Alto,Calif.) may also be useful within the scope of the present invention.Such devices 110 may be used as depicted in FIG. 9 for treating arespiratory ailment such as asthma. Optionally, the drug can bedelivered with the catheter 22 (as shown) or with the external sourcesof FIG. 13.

A combination of these non-invasive approaches may also be advantageousas shown in FIG. 15, wherein an non-invasive inhaler 110 is used todeliver the BoNT-LC to the target region (such as the lung), and theenergy is delivered to the target region by the non-invasive source 102such as the focused ultrasound (HIFU), stereotactic x-ray, or magneticresonance transmission as previously described. Due to its non-invasivetechnique, this approach may have broad appeal to a large patientpopulation, including pediatric use, on an outpatient basis in a clinicdesignated for the treatment of specific respiratory ailments.

In a further aspect of the present invention, the fragmented moleculeBoNT-LC may be delivered intravenously to a patient to achieve asystemic affect. A non-invasive energy application device, such as thosedescribed above, may then be targeted at the area of interest to poratethe target area, thereby locally delivering the BoNT-LC to the regionsufficiently porated by the applied energy.

Cosmetic and Myofacial Applications. For some conditions, it may bedesirable to apply the energy field from the surface of the skin toproduce a porative effect, while injecting the BoNT-LC fragment into thetargeted facial muscles as shown in FIG. 14. In operation, an injectiondevice 220 places the BoNT-LC in the muscle to be treated (targetregion), and an energy transmission device such as an ultrasonic pen 222with a single, or a series of ultrasonic elements located on the distalend and coupled to an energy transmission system 224, follows along thetarget region to controllably discharge the BoNT-LC fragments to thetargeted cells leaving a highly controlled treated region. In someinstances for treatments around the eye, it may be desirable to limitthe penetration of the BoNT-LC to dermal or subdermal layers. In theseapplications, BoNT-LC may be applied transdermally with ultrasoundassistance using techniques similar to those set forth in U.S. Pat. No.4,767,402 to Kost the contents of which is expressly incorporated hereinin its entirety or through transdermal electroporation.

Intraluminal Devices

It may further be advantageous to position catheters of the presentinvention through vessels in the body to direct them to various regionsto affect neurotransmitters in the cardiovascular system. Intraluminalcatheters such as those shown in United States Patent Applications2001/0044596 to Jaafar and 2002/0198512 to Seward, hereby incorporatedby reference in their entirety, may be used in this application of thepresent invention.

Treatment Enhancements

In some applications of the present invention, it may be desirable toassess the appropriate location for the therapy prior to treatment, thetherapeutic effect as it is delivered, and ultimately the resultingeffect. To achieve this, once the treatment device is in place adjacentthe tissue to be treated, the energy generator may be activated, causingan energized field to be generated in the target area. Prior toactivation of therapeutic voltages and agent, stimulation using one ormore electrodes may be used to elicit a nerve response or reflex. Byobserving the nerve response, a target treatment location can beconfirmed. Similarly, once the therapy has been delivered, a similarstimulation response may be sought, to determine presence or lack ofneurogenic response.

In operation, effects of electroporation and delivery of a therapeuticdose of BoNT LC may be selective due to the cellular structure andorientation of the targeted cells. For example, targeted cells may bepreferentially affected due to size, avoiding smaller or cross-orientedtissue cells.

In a further aspect of the present invention, the method of deliveringthe LC fragment of the BoNT molecule may include the use of a media thatcontains microspheres or microbubbles, such as Optison™ sold by GEHealthcare (www.amershamhealth-us.com/optison/). Delivery of anultrasound energy (or other form of energy, for example, laser, RF,thermal, energy) to the media causes the microspheres to rupture, whichcauses a release of energy toward the targeted region. Such a techniquemay assist in the desired porative effect by reducing the amount ofapplied energy required to create poration in the targeted cellmembrane. Bioeffects Caused by Changes in Acoustic Cavitation BubbleDensity and Cell Concentration: A Unified Explanation Based onCell-to-Bubble Ratio and Blast Radius, Guzman, et al. Ultrasound in Med.& Biol., Vol. 29, No. 8, pp. 1211-1222 (2003). In an alternativeembodiment, the LC fragment may actually be contained or encapsulatedwithin a microsphere to assist in delivery. Such enhancing elements maybe delivered prior to energy application or during energy application.

In a further aspect of the present invention, it may be advantageous toheat the targeted cells or surrounding tissue by either applying thermalenergy directly to the region, or directing a heated fluid, such assaline to the region through an injection element, to aid the cellporation process. Other substances may also be injected to aid in thetransmission of the BoNT-LC into the intracellular membrane, such asamino acids, detergents or other agents that may facilitate thecatalytic activity of the LC, in addition to the applied energy.

Referring now to FIGS. 15A and 15B, a balloon catheter 300 may bedelivered to a target site in the bronchus B of a lung (FIG. 15B).Typically, the catheter 300 will be delivered through an endoscope E,and the shaft 302 of the catheter will comprise at least one lumen forinflating the balloon 304. The inflation medium may carry the toxinfragment which is released through ports 306 formed in the balloonitself. Thus, inflation of the balloon both engages the ports againstthe wall of the bronchus B and provides the pressure necessary to infusethe neurotoxin fragments into the wall of the bronchus B. Usually,energy will be applied from electrodes 308 or other transducers locatedwithin the balloon 304.

Referring now FIGS. 16A and 16B, the catheter 400 may also be deliveredto a bronchus B of a lung through an endoscope E. Catheter shaft 402terminates with a delivery port 404 near its distal end. A deflectionballoon 406 (or other expandable element capable of pressing against thewall of the bronchus B to engage the port 404 against target tissue) isprovided on a side of the catheter shaft 402 which is opposite to thatof the port 404. Electrodes 408 are provided on either side of the port404 in order to deliver the poration energy into the target tissue.

Although various illustrative embodiments of the present invention aredescribed above, it will be evident to one skilled in the art thatvarious changes and modifications may be made without departing from thescope of the invention. It will also be apparent that various changesand modifications may be made herein without departing from theinvention. The appended claims are intended to cover all such changesand modifications that fall within the true spirit and scope of theinvention.

What is claimed is:
 1. A nerve modification device for altering nervefunction in a bronchial airway of a patient, the nerve modificationdevice comprising: a main catheter body configured to extend though atrachea into the bronchial airway; and at least one energy applicatorhaving at least one energy emitter configured to emit energy laterallyrelative to the main catheter body, wherein the nerve modificationdevice is adapted to deliver energy from the at least one energy emitterto produce an energy field concentrated in a target region in the wallof the bronchial airway in a first lateral direction from the maincatheter body to alter nerve cells within the target region.
 2. Thenerve modification device of claim 1, wherein the energy is at least oneof x-ray energy, radiofrequency energy, DC current, AC current,microwave energy, and ultrasound energy.
 3. The nerve modificationdevice of claim 1, wherein the at least one energy emitter comprises atleast one electrode.
 4. The nerve modification device of claim 3,wherein the energy is RF energy.
 5. The nerve modification device ofclaim 1, wherein the at least one energy emitter comprises at least oneultrasound transducer.
 6. The nerve modification device of claim 5,wherein the energy is ultrasound energy.
 7. The nerve modificationdevice of claim 1, wherein the energy applicator is configured to bepositionable in contact with a first portion of a circumference of theairway wall.
 8. A system for altering nerve function in a bronchialairway of a patient, the system comprising: an intraluminal catheterconfigured to be positioned within a bronchial airway of a patient, theintraluminal catheter including: a main catheter body, and a firstenergy emitter configured to emit energy laterally relative to the maincatheter body; and an energy generator operably coupled to the firstenergy emitter and configured to activate the first energy emitter,thereby causing an energy field to be generated in a target region inthe airway wall to alter nerve cells within the target region.
 9. Thesystem of claim 8, wherein the main catheter body is configured to bepositionable such that the first energy emitter is in contact with afirst portion of a circumference of the airway wall.
 10. The system ofclaim 8, further comprising: a second energy emitter operably coupled tothe energy generator, the second energy emitter being configured to bepositioned outside of the airway and remote from the target region, thetarget region being positioned between the first and second energyemitters such that activation of the first and second energy emitters bythe energy generator produces the energy field between the first andsecond emitters and within the target region.
 11. The system of claim10, wherein a placement of the first and second energy emitters relativeto each other controls the size and/or intensity of the energy field.12. The system of claim 8, the system further comprising: a secondenergy emitter operably coupled to the energy generator, such that anarrangement of the first and second energy emitters causes the energyfield produced therefrom to be concentrated in a lateral direction fromthe main catheter body.
 13. The system of claim 8, a second energyemitter operably coupled to the energy generator, such that anarrangement of the first and second energy emitters causes the energyfield produced therefrom to comprise a uniform energy field about themain catheter body.
 14. The system of claim 8, wherein the energy is atleast one of x-ray energy, radiofrequency energy, DC current, ACcurrent, microwave energy, and ultrasound energy.
 15. The system ofclaim 8, wherein the first energy emitter comprises an electrode. 16.The system of claim 15, wherein the energy is RF energy.
 17. The systemof claim 8, wherein the first energy emitter comprises an ultrasoundtransducer.
 18. A method, comprising: causing a nerve modificationdevice to be manufactured and made available to a user, the nervemodification device including a main catheter body and at least oneenergy applicator having at least one energy emitter; and providinginstructions to the user for use of the nerve modification device, theinstructions recorded on a tangible or non-transitory computer-readablemedium and including: positioning the nerve modification device at atreatment site in a bronchial airway of a patient; and causing the nervemodification device to deliver energy from the at least one energyemitter to produce an energy field concentrated in a target region inthe wall of the bronchial airway in a first lateral direction from themain catheter body to alter nerve cells within the target region. 19.The method of claim 18, wherein causing the nerve modification device todeliver energy from the at least one energy emitter comprises causingthe nerve modification device to deliver a pulse of radio frequencyenergy.
 20. The method of claim 18, wherein causing the nervemodification device to deliver energy from the at least one energyemitter comprises causing the nerve modification device to deliver oneof x-ray energy, radiofrequency energy, DC current, AC current,microwave energy, and ultrasound energy.